Targeting Ovarian Cancer Cells Overexpressing CD44 with Immunoliposomes Encapsulating Glycosylated Paclitaxel

Abstract

Paclitaxel (PTX) is one of the front-line drugs approved for the treatment of ovarian cancer. However, the application of PTX is limited due to the significant hydrophobicity and poor pharmacokinetics. We previously reported target-directed liposomes carrying tumor-selective conjugated antibody and encapsulated glycosylated PTX (gPTX-L) which successfully overcome the PTX limitation. The tubulin stabilizing activity of gPTX was equivalent to that of PTX while the cytotoxic activity of gPTX was reduced. In human ovarian cancer cell lines, SK-OV-3 and OVK18, the concentration at which cell growth was inhibited by 50% (IC50) for gPTX range from 15–20 nM, which was sensitive enough to address gPTX-L with tumor-selective antibody coupling for ovarian cancer therapy. The cell membrane receptor CD44 is associated with cancer progression and has been recognized as a cancer stem cell marker including ovarian cancer, becoming a suitable candidate to be targeted by gPTX-L therapy. In this study, gPTX-loading liposomes conjugated with anti-CD44 antibody (gPTX-IL) were assessed for the efficacy of targeting CD44-positive ovarian cancer cells. We successfully encapsulated gPTX into liposomes with the loading efficiency (LE) more than 80% in both of gPTX-L and gPTX-IL with a diameter of approximately 100 nm with efficacy of enhanced cytotoxicity in vitro and of convenient treatment in vivo. As the result, gPTX-IL efficiently suppressed tumor growth in vivo. Therefore gPTX-IL could be a promising formulation for effective ovarian cancer therapies.

CD44: A Multifunctional Mediator of Cancer Progression

“…In addition, the anti-CD44 mAb A3D8 enhanced apoptosis in acute myeloid leukaemia cells through caspase-8 activation by binding to CD44s protein [ 210 ]. In human ovarian cancer cell lines overexpressing CD44, the encapsulated glycosylated paclitaxel liposomes (gPTX-L) conjugated with anti-CD44 antibody efficiently enhanced cytotoxicity in vitro and in vivo, suppressing tumour growth in vivo [ 211 ].…”

Natural products and their derivatives: Promising modulators of tumor immunotherapy

“…Many studies demonstrated that systemic delivery of paclitaxel using a nanocarrier or receptor resulted in a significantly improved antitumor response. 108,157 For example, paclitaxel derivative-loaded nanoparticles showed lower cytotoxicity toward bone marrow-derived macrophages (BMDMs) than free paclitaxel, up-regulating the CD11b expression in BMDMs. This nanoparticle polarized macrophages toward M1 and inhibited their M2 dif-ferentiation, both on phenotypic and functional levels.…”

“…Therefore, many vectors have been used to study the reduction of paclitaxel toxicity. Many studies demonstrated that systemic delivery of paclitaxel using a nanocarrier or receptor resulted in a significantly improved antitumor response 108,157 . For example, paclitaxel derivative‐loaded nanoparticles showed lower cytotoxicity toward bone marrow‐derived macrophages (BMDMs) than free paclitaxel, up‐regulating the CD11b expression in BMDMs.…”

Dual-Targeting and Stimuli-Triggered Liposomal Drug Delivery in Cancer Treatment

“…Standard histological analyses showed that SIL-treated rats exhibited numerous granulomas, whereas the livers of SSIL2-treated animals exhibited only a few isolated granulomas. Khayrani et al 39 assessed the therapeutic efficacy of glycosylated paclitaxel (gPTX)-loaded liposomes functionalized with anti-CD44 antibody (gPTX-IL). The in vitro cytotoxicity of gPTX-IL was tested in SK-OV-3 and OVK18 ovarian cancer cell lines.…”